Compounds based on the ergoline ring system: ##STR1## have a suprising variety of pharmaceutical activities. For example, many of the amides of lysergic acid, which is 8.beta.-carboxy-6-methyl-9-ergolene, have valuable and unique pharmacologic properties. The trivial name "ergoline" is given to the above structure and the 9,10 double bonded compound--related to lysergic acid-- is called a 9-ergolene rather than a 9,10-didehydro-ergoline. The name D-ergoline or D-8-ergolene or D-9-ergolene is used herein in naming specific compounds. The letter "D" indicates that the C-5 carbon atom configuration has the absolute stereochemistry designated as R and that the hydrogen is .beta.--above the plane of the ring system. However, modern usage has tended to omit the "D", on the ground that the newly synthesized ergolines or ergolenes are universally derivatives of natural products such as lysergic acid or elymoclavine, both of which have R stereochemical-- "D" series--configuration and in which the stereochemical integrity at C-5 is maintained during various synthetic procedures. It should be understood that all of the compounds and the classes of ergolines or ergolenes disclosed herein also have the R stereochemical configuration, whether or not the specific or generic name is preceded by a "D".
Among the pharmacologically active amides of lysergic acid are included naturally-occurring oxytoxic alkaloids--ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc.--and synthetic oxytocics such as methergine as well as the synthetic hallucinogen lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves.
Recently, it has been found by Clemens, Semonsky, Meites, and their various co-workers that many ergot-related drugs have activity as prolactin inhibitors. Ergocornine, dihydroergocornine, 2-bromo-.alpha.-ergokryptine and D-6-methyl-8-cyanomethylergoline (Semonsky et al U.S. Pat. No. 3,732,231) are examples of such drugs. References embodying some of the newer findings in the field of ergoline and ergolene chemistry include the following: Nagasawa and Meites, Proc. Soc. Exp't'l. Biol. Med., 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech. Chem. Commun., 33, 577 (1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971); Schaar and Clemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp. Biol. Med., 139, 659-662 (1972), Bach and Kornfeld, Tetrahedron Letters, 3225 (1974) and Sweeney, Clemens, Kornfeld and Poore, 64th Annual Meeting, American Association for Cancer Research, April 1973. Recently issued patents in the field of the ergolines or of lysergic acid derivatives include the following: U.S. Pat. No. 3,923,812, U.S. Pat. No. 3,929,796, U.S. Pat. No. 3,944,582, U.S. Pat. No. 3,934,772, U.S. Pat. No. 3,954,988, U.S. Pat. No. 3,957,785, U.S. Pat. No. 3,966,739, U.S. Pat. No. 3,968,111, U.S. Pat. No. 4,001,242. Many other related and older patents can be found in Patent Office Classification Files 260-256.4 and 260-285.5.
U.S. Pat. No. 4,166,182 issued Aug. 28, 1979 (filed February 8, 1978) discloses and claims D-6-n-propyl-8.beta.-methoxymethylergoline and D-6-n-propyl-8.beta.-methylmercaptomethylergoline, among other compounds. The latter drug has been given the generic name pergolide and is presently undergoing a clinical trial as a prolactin inhibitor and in the treatment of Parkinsonism.
Stutz et al J. Med. Chem., 21, 754 (1978) describes the preparation of a group of 6-methyl-8.alpha.-arylthiomethylergolines which were found to be dopaminergic agents with a potential in the treatment of Parkinson's syndrome. The 8.alpha.-isomer of the Semonsky et al compound, 6-methyl-8.beta.-cyanomethylergoline, was also prepared and "--- was rather unexpectedly found to be a highly active dopaminergic stimulant in the Ungerstedt test ---.". 6-Methyl-8.beta.-methylthiomethyl ergolines are disclosed and claimed in U.S. Pat. Nos. 3,959,288 and 3,901,894 respectively as prolactin inhibitors.
Parkinson's disease, also known as paralysis agitans or shaking palsy, was first described in the late 18th century. It is characterized by tremor, muscular rigidity and loss of postural reflexes. The disease usually progresses slowly with intervals of 10 to 20 years elapsing before the symptoms cause incapacity. The terms "Parkinsonism" and "the Parkinsonian syndrome" include not only Parkinson's disease but also drug-induced Parkinsonism and post-encephalitic Parkinsonism. Treatment of Parkinsonism involves symptomatic, supportive and palliative therapy. Parkinson's disease has been treated with various anticholinergic agents, which agents have a greater beneficial effect on rigidity and akinesia than on tremor. More recently l-dopa (1-dihydroxyphenylalanine) has been used because of the finding that there is an altered catecholamine content in the brains of patients afflicted with Parkinsonism. Unfortunately, l-dopa is rapidly metabolized. It has been suggested, therefore, that monoamineoxidase inhibitors be used to retard the degradation of cerebral catechol amines. The use of l-dopa with a decarboxylase inhibitor was also designed to increase the level of l-dopa in the brain and hopefully thereby to alleviate the symptoms of Parkinsonism. It has also been suggested (by Corrodi and coworkers) that certain ergot derivatives, such as the naturally occurring alkaloid, ergocornine, are direct dopamine receptor stimulants of long duration and may therefore prove to be of value in the treatment of Parkinson's disease [see J. Pharm. Pharmac., 25, 409 (1973)]. Johnson et al. in Experientia, 29, 763 (1973) discuss the evidence of Corrodi et al. that ergocornine and 2-bromo-.alpha.-ergokryptine simulate dopamine receptors and extended their observations to other ergot alkaloids (see also Brit. J. Pharm., 56, 59 (1976). Trever W. Stone writing in Brain Research, 72, 1977 (1974) verified the above experiments and produced further evidence that ergot alkaloids have a dopamine receptor stimulating action.